Passive smoking has been linked to lung cancer risk in non-smokers. We propose to further investigate this association through a study on the debrisoquine metabolic genotypes in women with lung cancer. A genetic polymorphism in the P-45O/CYP2D6 debrisoquine hydroxylase gene has been shown to influence lung cancer susceptibility. Persons homozygous for a defective hydroxylase gene ("poor metabolizers", PM) are unable to metabolize debrisoquine, nor activate efficiently certain pro- carcinogens including a nicotine derivative found in tobacco smoke. Eight to 10 percent of Caucasians inherit this trait recessively, but this figure is only 2-3% in lung cancer patients. If the PM frequency in non- smokers with lung cancer, and particularly those heavily exposed to passive smoke, is similar (2-3%), this would be a strong argument in favor of the hypothesis that indirect smoke exposure is etiologically relevant and acts through the same cellular mechanism as in smokers. In the proposed study, subjects will be drawn from completed interview studies of women with lung cancer and classified according to exposure status: smoking (N=250) vs non-smoking (N=350), and within the latter group heavily (N=175) vs lightly (N=175) passively exposed non-smokers. Tumor material will be available on all patients, and a PCR-based genetic assay will be performed to identify the genotypes. This assay can identify the normal genotype in 100% and distinguish the PMs in >90% of cases. This study, correlating epidemiological data with molecular biology analysis, may give us some insight into the molecular mechanisms of mutagenesis associated with passive smoking.